US4089961A - Antipsychotically useful quinolizidylidene derivatives of xanthenes, thioxanthenes and dibenzoxepins - Google Patents

Antipsychotically useful quinolizidylidene derivatives of xanthenes, thioxanthenes and dibenzoxepins Download PDF

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Publication number
US4089961A
US4089961A US05/739,688 US73968876A US4089961A US 4089961 A US4089961 A US 4089961A US 73968876 A US73968876 A US 73968876A US 4089961 A US4089961 A US 4089961A
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US
United States
Prior art keywords
compound
quinolizidine
ylidene
pharmaceutically acceptable
acid addition
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Expired - Lifetime
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US05/739,688
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English (en)
Inventor
Carl Kaiser
John Joseph Lafferty
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SmithKline Beecham Corp
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SmithKline Corp
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Priority to US05/739,688 priority Critical patent/US4089961A/en
Priority to GB44564/77A priority patent/GB1591126A/en
Priority to JP13213977A priority patent/JPS5359695A/ja
Priority to FR7732991A priority patent/FR2370050A1/fr
Priority to DE19772749957 priority patent/DE2749957A1/de
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Publication of US4089961A publication Critical patent/US4089961A/en
Assigned to SMITHKLINE BECKMAN CORPORATION reassignment SMITHKLINE BECKMAN CORPORATION CHANGE OF NAME (SEE DOCUMENT FOR DETAILS). EFFECTIVE DATE: 03/04/82 Assignors: SMITHKLINE CORPORATION
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D455/00—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
    • C07D455/02—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing not further condensed quinolizine ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D313/00—Heterocyclic compounds containing rings of more than six members having one oxygen atom as the only ring hetero atom
    • C07D313/02—Seven-membered rings
    • C07D313/06—Seven-membered rings condensed with carbocyclic rings or ring systems
    • C07D313/10—Seven-membered rings condensed with carbocyclic rings or ring systems condensed with two six-membered rings
    • C07D313/12—[b,e]-condensed

Definitions

  • This invention relates to novel pharmaceutical compositions containing as an active ingredient compounds which produce antipsychotic activity essentially free of extrapyramidal symptoms and to a method of producing antipsychotic activity essentially free of extrapyramidal symptoms which comprises administering nontoxic effective quantities of said active ingredients to an animal.
  • Extrapyramidal symptoms are some of the most undesirable and common side effects produced by antipsychotic or neuroleptic drugs.
  • the compounds which are the active ingredients used in the compositions and methods of this invention have a neuropharmacological profile indicative of potent antipsychotic activity but essentially no liability to produce EPS.
  • the active ingredients used in the compositions and methods of this invention are quinolizidylidene derivatives of xanthenes, thioxanthenes and dibenzoxepins.
  • the compounds of this invention may exist as geometrical isomers, i.e., the bicyclic quinolizidine system may exist as cis or trans isomers depending on the nature of fusion of the two ring systems and in those instances where X is not equal to H additional geometrical isomers are possible depending upon theorientation of the bicyclic ylidene structure.
  • the bulk of the tetramethylene fusion to the piperidylidene system is oriented toward the side of the X substitution.
  • the other isomer has the bicyclic bulk directed away from the nuclear substituent X.
  • X represents hydrogen, halogen, thiomethyl cyano, lower alkyl of from 1 to 3 carbon atoms, methoxy, trifluoromethyl, trifluoromethylthio, dimethylaminosulfonyl or acetyl.
  • the nontoxic pharmaceutically acceptable acid addition salts of the compounds of formulas I and II are similarly useful in the compositions and methods of this invention. Such salts are easily prepared by methods known to the art.
  • the base is reacted with either the calculated amount of organic or inorganic acid in aqueous miscible solvent, such as acetone or ethanol, with isolation of the salt by concentration and cooling or an excess of the acid in aqueous immiscible solvent, such as ethyl ether or chloroform, with the desired salt separating directly.
  • aqueous miscible solvent such as acetone or ethanol
  • organic salts are those with maleic, fumaric, benzoic, ascorbic, pamoic, succinic, bismethylenesalicylic, acetylsalicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, cyclohexylsulfamic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic and theophyllineacetic acids as well as with 8-halotheophyllines, for example 8-bromotheophylline.
  • inorganic salts are those with hydrochloric, hydrobromic, sulfuric, phosphoric and nitric acids.
  • these salts may also be prepared by the classical method of double decomposition of appropriate salts which is well known to the art.
  • the compounds of formulas I and II are generally prepared from an appropriately substituted xanthone, thioxanthone or dibenzoxepinone by reaction with a quinolizidinyl magnesium halide in an inert organic solvent such as ether, for example ethyl ether, dioxane or tetrahydrofuran, at from room temperature to the reflux temperature of the solvent, for from 30 minutes to 4 hours.
  • ether for example ethyl ether, dioxane or tetrahydrofuran
  • the tricyclic carbinol intermediate is dehydrated to the olefin under acid or thermal conditions.
  • Compounds of formulas I and II in which X represents cyano are prepared by treatment of the corresponding derivatives where X is bromo with cuprous cyanide in dimethformamide.
  • Compounds of formula I and II in which X represents acetyl are prepared by addition of a methyl magnesium halide to the cyano compounds followed
  • Amphetamine which releases dopamine and norepinephrine from catecholaminergic neurons, causes these rats to rotate unidirectionally toward the side of the lesion. Since there is a much larger amount of dopamine to be released by amphetamine from the intact nigrostriatal neurons on the non-lesioned side than from those remaining on the lesioned side, the rotational behavior is apparently due to a preponderance of activation of striatal dopamine receptors on the intact side. The ability of a drug to antagonize the rotational behavior is therefore a measure of its ability to block striatal dopamine receptors and is indicative of its potential to produce EPS.
  • the ratio of its ED 50 (i.p.) for antagonism of amphetamine-induced rotation to its ED 50 (i.p.) for blockage of shock avoidance acquisition in the rat a procedure for assessing antipsychotic activity, (R/A ratio) is calculated.
  • the ED 50 values of some clinically established antipsychotics in the avoidance and rotational tests and the R/A ratios are presented in Table I.
  • Chlorpromazine has a R/A ratio of 1.3.
  • Antipsychotics that have a considerably greater propensity to cause EPS than chlorpromazine, e.g., trifluoperazine, haloperidol and pimozide have ratios of 0.3 to 0.5.
  • Preferred compounds of this invention are the geometrical isomers of 3-(2-chlorothioxanthen-9-ylidene)quinolizidine.
  • One isomer, having a melting point of 218-220° C. has an ED 50 of 1.7 mg./kg. (i.p.) for blockade of shock avoidance acquisition and ED 50 of 8.2 mg./kg. (i.p.) for antagonism of amphetamine-induced rotation resulting in an R/A ratio of 4.8.
  • the other isomer which has a melting point of 214°-217° C., has an ED 50 of 0.7 mg./kg. (i.p.) for blockade of shock avoidance acquisition and an ED 50 of 2.3 mg./kg. (i.p.) for antagonism of amphetamine induced rotation resulting in an R/A ratio of 3.3.
  • compositions of this invention are prepared in conventional dosage unit forms by incorporating a compound of formulas I or II or a pharmaceutically acceptable salt thereof, in a nontoxic amount sufficient to produce antipsychotic activity essentially free of extrapyramidal symptoms in an animal, with a nontoxic pharmaceutical carrier according to accepted procedures.
  • a nontoxic pharmaceutical carrier according to accepted procedures.
  • the compositions will contain the active ingredient in an active but nontoxic amount selected from about 1 mg. to about 300 mg., advantageously from about 5 mg. to about 200 mg., of active ingredient per dosage unit.
  • the pharmaceutical carrier employed may be, for example, either a solid or liquid, giving rise to a wide variety of pharmaceutical forms. If a solid pharmaceutical carrier is used, such as lactose, magnesium stearate, terra alba, sucrose, talc, stearic acid, gelatin, agar, pectin, acacia and the like, the composition can be tableted, used as a pharmaceutical powder, placed in a hard gelatin capsule or in the form of a troche or lozenge. The amount of solid carrier will vary widely but preferably will be from about 25 mg. to about 1 g.
  • a liquid pharmaceutical carrier such as syrup, peanut oil, olive oil, sesame oil, water and the like
  • the composition will be in the form of a soft gelatin capsule, syrup, emulsion or a liquid suspension.
  • the carrier or diluent may include a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax.
  • Parenteral dosage forms such as for intramuscular administration are obtained by dissolving a water soluble salt of the active medicament in water or saline solution in a concentration such that 1 ml. of the solution contains from about 2 mg. to about 50 mg. of active ingredient. The solution can then be filled into single ampuls or multiple dose vials.
  • a compound of formula I or II or a nontoxic acid addition salt thereof is administered internally to an animal in need of antipsychotic activity, preferably with a pharmaceutical carrier, in a nontoxic amount sufficient to produce antipsychotic activity essentially free of extrapyramidal symptoms.
  • the active medicament preferably in a dosage unit, is administered orally or intramuscularly in an active, nontoxic quantity selected from about 1 mg. to about 300 mg. of the parent chemical of formula I or II.
  • Advantageously equal doses will be administered until a desired effect is obtained, such as two or three times a day.
  • the daily dosage is selected from about 2 mg. to about 900 mg. of active medicament, advantageously from about 10 mg. to about 600 mg.
  • a stirred mixture of 3.96 g. (0.01 mole) of 3-(2-bromothioxanthen-9-ylidene)quinolizidine, 2.70 g. (0.015 mole) of cuprous cyanide, 50 mg. of cupric sulfate, 50 mg. of sodium cyanide in 40 ml. of dimethylformamide is heated at reflux temperature for eighteen hours.
  • the cooled reaction mixture is then poured into 200 ml. of 1 M sodium cyanide.
  • the resulting mixture is extracted with ether. After being washed with an aqueous solution of sodium cyanide and water, the ether solution is dried over magnesium sulfate. The dried solution is concentrated.
  • the ether (22.6 g., 0.1 mole) was refluxed in dry xylene with a mixture of 65 g. of Super-cel and 65 g. of phosphorus pentoxide for seventeen hours.
  • the reaction mixture was filtered.
  • the filter cake was washed with xylene and ether.
  • the combined filtrates were concentrated to give a solid which was recrystallized from ethanol to afford crystals of 2-methyldibenzo[b,e]oxepin-11-one, m.p. 100°-103° C.
  • sucrose, calcium sulfate and quinolizidine are thoroughly mixed and granulated with hot 10% gelatin solution.
  • the wetted mass is passed through a No. 6 standard mesh screen onto drying trays.
  • the granules are dried at 120° F. and passed through a No. 20 mesh screen.
  • These granules are then mixed with starch, talc and stearic acid, passed through a No. 60 mesh screen and then compressed into tablets.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Psychiatry (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
US05/739,688 1976-11-08 1976-11-08 Antipsychotically useful quinolizidylidene derivatives of xanthenes, thioxanthenes and dibenzoxepins Expired - Lifetime US4089961A (en)

Priority Applications (5)

Application Number Priority Date Filing Date Title
US05/739,688 US4089961A (en) 1976-11-08 1976-11-08 Antipsychotically useful quinolizidylidene derivatives of xanthenes, thioxanthenes and dibenzoxepins
GB44564/77A GB1591126A (en) 1976-11-08 1977-10-26 Quinolizidines
JP13213977A JPS5359695A (en) 1976-11-08 1977-11-02 Quinolidene derivative of xanthene * thioxanthene and dibenzoxepine
FR7732991A FR2370050A1 (fr) 1976-11-08 1977-11-03 Derives quinolizidylideniques de xanthenes, thioxanthenes et dibenzoxepines, leur procede de preparation et leur application en therapeutique
DE19772749957 DE2749957A1 (de) 1976-11-08 1977-11-08 Chinolizidyliden-derivate von xanthenen, thioxanthenen und dibenzoxepinen und deren salze, verfahren zu ihrer herstellung und ihre verwendung als wirkstoffe mit antipsychotischer aktivitaet

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US05/739,688 US4089961A (en) 1976-11-08 1976-11-08 Antipsychotically useful quinolizidylidene derivatives of xanthenes, thioxanthenes and dibenzoxepins

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US4089961A true US4089961A (en) 1978-05-16

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US (1) US4089961A (de)
JP (1) JPS5359695A (de)
DE (1) DE2749957A1 (de)
FR (1) FR2370050A1 (de)
GB (1) GB1591126A (de)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BG30018A3 (en) * 1977-05-16 1981-03-16 Hokuriku Pharmaceutical Co.,Jp Method for obtaining of substituated hinolisidine and indolisidine derivatives
DE19848200A1 (de) * 1998-10-20 2000-04-27 Basf Ag Verfahren zur Trocknung von Phenoxymethylbenzoesäuren
US7238835B2 (en) 2003-12-22 2007-07-03 Sanofi-Aventis Deutschland Gmbh Process for the preparation of substituted 2-(phenoxymethyl) benzoic acids
CN113754527B (zh) * 2021-09-07 2024-01-12 山东京博农化科技股份有限公司 一种醚菌酯中间体的合成方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2985660A (en) * 1960-04-29 1961-05-23 Lakeside Lab Inc 5-heterocyclic-5h-dibenzo [a, d] cycloheptenes
US3153652A (en) * 1964-10-20 Certificate of correction
US3527763A (en) * 1965-09-01 1970-09-08 Koninklijke Pharma Fab Nv 5-hydroxy-dibenzocyclohepten-5-yl-carboxylates

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ZA756550B (en) * 1974-11-06 1976-09-29 Smithkline Corp Pharmaceutical compositions and method of producing antipsychotic activity without extrapyramidal symptoms

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3153652A (en) * 1964-10-20 Certificate of correction
US2985660A (en) * 1960-04-29 1961-05-23 Lakeside Lab Inc 5-heterocyclic-5h-dibenzo [a, d] cycloheptenes
US3527763A (en) * 1965-09-01 1970-09-08 Koninklijke Pharma Fab Nv 5-hydroxy-dibenzocyclohepten-5-yl-carboxylates

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Chemical Abstracts, 67, 32856h (1967) [Boldo, V. et al., Ann. Chim. (Rome), 56(12), 1603-1613 (1966)]. *

Also Published As

Publication number Publication date
DE2749957A1 (de) 1978-05-11
GB1591126A (en) 1981-06-17
FR2370050A1 (fr) 1978-06-02
FR2370050B1 (de) 1981-07-03
JPS5359695A (en) 1978-05-29

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